GNLY+CD8+ T cells bridge premature aging and persistent inflammation in people living with HIV.

People living with HIV (PLWH) exhibit accelerated aging, characterized by systemic inflammation, termed "inflammaging." While T-cell expansion is prevalent in PLWH, its connection to inflammaging remains unclear. In this study, we analyzed the TCRβ repertoire of 257 healthy controls (HC) and 228 PLWH, revealing pronounced T cell clonal expansion in PLWH. The expansion was only partially reversed following antiretroviral therapy (ART) and closely associated with ART duration, CD4+ T and CD8+ T cell counts and the CD4/CD8 ratio. TCR-based age modeling showed a continuous accelerated trajectory of aging in PLWH, especially in younger individuals, in stark contrast to the nonlinear aging acceleration pattern seen in HC. Furthermore, using single-cell RNA combined TCR sequencing and in vitro experiments, we identified GNLY+CD8+ T cells as the primary population driving clonal expansion and maintenance in PLWH. These cells are characterized by high cytotoxicity and low exhaustion and are activated by interleukin-15 (IL-15) in vitro. Notably, GNLY+CD8+ T cells predominantly express the pro-inflammatory 15 kDa form of granulysin(GNLY). The supernatant from IL-15-stimulated CD8+ T cells induces monocytes to secrete inflammatory factors and disrupts the integrity of intestinal epithelial cells, which can be partially restored by the anti-GNLY antibodies. These findings identify GNLY+CD8+ T cells as the central drivers of persistent clonal expansion, highlighting their crucial role for mitigating inflammaging in PLWH.